Modelling HIV in the injecting drug user population and the male homosexual population in a developed country context.
In many high income countries men who have sex with men (MSM) and injecting drug users (IDUs) are the two groups with the highest HIV prevalence. Yet these two groups are not mutually exclusive, and those MSM who are also IDUs (MSM-IDUs) may be particularly vulnerable to HIV infection. This may be particularly relevant to the IDU population in countries, like the UK, with a much lower HIV prevalence amongst IDUs than MSM, as the MSM-IDUs could provide a route of HIV infection into the IDU population. In this research two alternative modelling approaches that describe the transmission dynamics of HIV within the IDU, MSM, and heterosexual populations are proposed. These models are constructed with two aims. The first is to investigate the possible impact of interventions that target HIV transmission in the MSM and IDU populations, and the second aim is to investigate the impact of the model structure on the model results. An examination of the assortativity of mixing between risk groups is also undertaken. The models are parameterised for England and Wales. While the MSM-IDU population is small, targeting MSM-IDUs was the most efficient intervention strategy in terms of cases averted per 100 individuals targeted with the intervention. Sensitivity analysis showed that variations in the assumed assortativity of mixing between the population groups in both models have a large impact on model results. This means that to generate quantitatively robust estimates for the impact of different intervention strategies it will be necessary to obtain estimates for assortativity values through empirical work.


Using narrative inquiry to listen to the voices of adolescent mothers in relation to their use of social networking sites (SNS).
This article presents a discussion highlighting the relevance and strengths of using narrative inquiry to explore experiences of social networking site (SNS) use by adolescent mothers. Narrative inquiry as a method reveals truths about holistic human experience. Knowledge gleaned from personal narratives informs nursing knowledge and clinical practice. This approach gives voice to adolescent mothers in relation to their experiences with SNS as a means of providing social support. Discussion paper. This paper draws and reflects on the author's experiences using narrative inquiry and is supported by literature and theory. The following databases were searched: CINAHL, Cochrane Library, Medline, Scopus, ERIC, ProQuest, PsychINFO, Web of Science and Health Collection (Informit). Key terms and Boolean search operators were used to broaden the search criteria. Search terms included: adolescent mother, teenage mother, "social networking sites", online, social media, Facebook, social support, social capital and information. Dates for the search were limited to January 1995-June 2017. Narrative research inherently values the individual "story" of experience. This approach facilitates rapport building and methodological flexibility with an often difficult to engage sample group, adolescents. Narrative inquiry reveals a deep level of insight into social networking site use by adolescent mothers. The flexibility afforded by use of a narrative approach allows for fluidity and reflexivity in the research process.


Expression of interleukin-8 and monocyte chemotactic protein-1 in adenomyosis.
To clarify the inflammatory nature of adenomyosis, we aimed to investigate the expression of interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) by immunohistochemistry to determine their putative role in pathophysiology of adenomyosis. Adenomyosis samples, with their eutopic endometrium, were collected from 30 women undergoing hysterectomy. Endometrium from 27 women without adenomyosis were also collected as a control group. Samples were grouped according to the menstrual cycle phase and examined by immunohistochemistry for IL-8 and MCP-1. In normal endometrium, secretory phase samples expressed higher levels of epithelial IL-8 than in proliferative phase samples (P = 0.01), and we observed a trend for an increased epithelial MCP-1 expression in the secretory phase samples compared with the proliferative phase samples (P = 0.07). Endometrial samples of women with adenomyosis did not show the same cyclic variation. In the secretory phase, eutopic endometrium of women with adenomyosis expressed lower levels of epithelial IL-8 and MCP-1 compared with normal endometrium (P < 0.05). The expression of epithelial IL-8 and MCP-1 was higher in the adenomyosis foci than the eutopic endometrium (P < 0.05). These findings may indicate that an intrinsic abnormality of inflammatory response may be present in eutopic endometrium of women with adenomyosis, and IL-8 and MCP-1 may contribute to the pathophysiology of adenomyosis.


Internet-based interactive health intervention for the promotion of sensible drinking: patterns of use and potential impact on members of the general public.
Heavy drinking is responsible for major health and social problems. Brief interventions have been shown to be effective, but there have been difficulties in reaching those who might benefit from them. Pilot studies have indicated that a Web-based intervention is likely to be acceptable to heavy drinkers and may produce some health benefits. However, there are few data on how many people might use such a program, the patterns of use, and potential benefits. The aim was to examine the demographic characteristics of users of a free, Web-based, 6-week intervention for heavy drinkers and to describe the methods by which users identified the site, the pattern of site use and attrition, the characteristics associated with completing the program, and the self-reported impact on alcohol-related outcomes. Cohort study. Visitors to the Web site were offered screening with the Fast Alcohol Screening Test, and those scoring above the cutoff for risky drinking were invited to register with the program. Demographic information was collected routinely at registration, and questionnaires were completed at the end of weeks 1 and 6. The outcome measures assessed dependency (Short Alcohol Dependency Data Questionnaire), harms (modified Alcohol Problems Questionnaire), and mental health (Clinical Outcomes in Routine Evaluation-Outcome Measure). The records of 10,000 users were analyzed. The mean age was 37.4 years, 51.1% were female, 37.5% were single, and 42.4% lived with children. The majority were White British, lived in the United Kingdom, and reported occupations from the higher socioeconomic strata. Over 70% connected to the Down Your Drink (Down Your Drink) site from another Internet-based resource, whereas only 5.8% heard about the site from a health or other professional. Much of the Web site use (40%) was outside normal working hours. Attrition from the program was high, with only 16.5% of registrants completing the whole 6 weeks. For those who completed the program, and the final outcome measures, measures of dependency, alcohol-related problems, and mental health symptoms were all reduced at week 6. The Web-based intervention was highly used, and those who stayed with the program showed significant reductions in self-reported indicators of dependency, alcohol-related problems, and mental health symptoms; however, this association cannot be assumed to be causal. Programs of this type may have the potential to reach large numbers of heavy drinkers who might not otherwise seek help. There are significant methodological challenges and further research is needed to fully evaluate such interventions.


Complete genome sequence of Vibrio anguillarum strain NB10, a virulent isolate from the Gulf of Bothnia.
Vibrio anguillarum causes a fatal hemorrhagic septicemia in marine fish that leads to great economical losses in aquaculture world-wide. Vibrio anguillarum strain NB10 serotype O1 is a Gram-negative, motile, curved rod-shaped bacterium, isolated from a diseased fish on the Swedish coast of the Gulf of Bothnia, and is slightly halophilic. Strain NB10 is a virulent isolate that readily colonizes fish skin and intestinal tissues. Here, the features of this bacterium are described and the annotation and analysis of its complete genome sequence is presented. The genome is 4,373,835 bp in size, consists of two circular chromosomes and one plasmid, and contains 3,783 protein-coding genes and 129 RNA genes.


Effects of a randomized controlled recurrent fall prevention program on risk factors for falls in frail elderly living at home in rural communities.
Falling can lead to severe health issues in the elderly and importantly contributes to morbidity, death, immobility, hospitalization, and early entry to long-term care facilities. The aim of this study was to devise a recurrent fall prevention program for elderly women in rural areas. This study adopted an assessor-blinded, randomized, controlled trial methodology. Subjects were enrolled in a 12-week recurrent fall prevention program, which comprised strength training, balance training, and patient education. Muscle strength and endurance of the ankles and the lower extremities, static balance, dynamic balance, depression, compliance with preventive behavior related to falls, fear of falling, and fall self-efficacy at baseline and immediately after the program were assessed. Sixty-two subjects (mean age 69.2±4.3 years old) completed the program--31 subjects in the experimental group and 31 subjects in the control group. When the results of the program in the 2 groups were compared, significant differences were found in ankle heel rise test, lower extremity heel rise test, dynamic balance, depression, compliance with fall preventative behavior, fear of falling, and fall self-efficacy (p<0.05), but no significant difference was found in static balance. This study shows that the fall prevention program described effectively improves muscle strength and endurance, balance, and psychological aspects in elderly women with a fall history.


Repression of colony formation reversed by antiserum to mouse thymocytes.
Marrow cells derived from C57BL/6 mice form many fewer splenic colonies in irradiated C57BL/6 x C3H F1 hybrid recipients than in irradiated C57BL/6 recipients (repression of colony formation). This effect is reversed by treatment of the hybrid recipients with active antiserum to mouse thymocytes. The repression phenomenon cannot readily be explained in immunological terms; hence the effect of the antilymphocyte serum on this phenomenon may not result from immunosuppression in the usual sense.


Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex.
The complex containing the Mre11, Rad50, and Nbs1 proteins (MRN) is essential for the cellular response to DNA double-strand breaks, integrating DNA repair with the activation of checkpoint signaling through the protein kinase ATM (ataxia telangiectasia mutated). We demonstrate that MRN stimulates the kinase activity of ATM in vitro toward its substrates p53, Chk2, and histone H2AX. MRN makes multiple contacts with ATM and appears to stimulate ATM activity by facilitating the stable binding of substrates. Phosphorylation of Nbs1 is critical for MRN stimulation of ATM activity toward Chk2, but not p53. Kinase-deficient ATM inhibits wild-type ATM phosphorylation of Chk2, consistent with the dominant-negative effect of kinase-deficient ATM in vivo.


Pharmacokinetics and efficacy of a direct switch from conventional depot to risperidone long-acting injection in Chinese patients with schizophrenic and schizoaffective disorders.
This 12-week open-label study was designed to investigate the pharmacokinetics and efficacy of a direct switch from a conventional depot to long-acting injectable risperidone in patients with schizophrenia and schizoaffective disorder. Men or women from 18 to 65 years old with a diagnosis of schizophrenia or schizoaffective disorder were eligible for participation if they had been treated with conventional depot for at least 8 weeks before study entry. Intramuscular long-acting risperidone was administered starting from 25 mg, with the dose flexibly adjusted every two weeks for 12 weeks from week 4. Of the 25 patients enrolled in this study, 21 completed at least one post-baseline assessment and were thus included in the analysis. The mean serum concentration of risperidone plus 9-hydroxyrisperidone was 29.1 ng/mL at the 12th week after switching, with an average injection dose of 31.25 mg long-acting risperidone every two weeks. The levels of active moiety of risperidone seemed to be higher in Chinese patients compared to those in Caucasian patients. Positive and Negative Syndrome Scale total scores (from 67.5 to 56.4; P = 0.002), scores for negative symptoms (P = 0.006) and general symptoms (P = 0.001) were improved significantly 12 weeks after the switch. Mean Extrapyramidal Symptom Rating Scale scores were improved significantly from 20.1 to 5.5 (P < 0.001). Significantly decreased levels of cholesterol and triglyceride were found at the 12th week. The levels of fasting glucose, low-density lipoprotein, high-density lipoprotein and bodyweight remained unchanged. These findings suggest that switching from conventional depot to long-acting risperidone is feasible with the advantage of symptom reduction and side-effect profile decrement.


Hoxb8 intersection defines a role for Lmx1b in excitatory dorsal horn neuron development, spinofugal connectivity, and nociception.
Spinal cord neurons respond to peripheral noxious stimuli and relay this information to higher brain centers, but the molecules controlling the assembly of such pathways are poorly known. In this study, we use the intersection of Lmx1b and Hoxb8::Cre expression in the spinal cord to genetically define nociceptive circuits. Specifically, we show that Lmx1b, previously shown to be expressed in glutamatergic dorsal horn neurons and critical for dorsal horn development, is expressed in nociceptive dorsal horn neurons and that its deletion results in the specific loss of excitatory dorsal horn neurons by apoptosis, without any effect on inhibitory neuron numbers. To assess the behavioral consequences of Lmx1b deletion in the spinal cord, we used the brain-sparing driver Hoxb8::Cre. We show that such a deletion of Lmxb1 leads to a robust reduction in sensitivity to mechanical and thermal noxious stimulation. Furthermore, such conditional mutant mice show a loss of a subpopulation of glutamatergic dorsal horn neurons, abnormal sensory afferent innervations, and reduced spinofugal innervation of the parabrachial nucleus and the periaqueductal gray, important nociceptive structures. Together, our results demonstrate an important role for the intersection of Lmx1b and Hoxb8::cre expression in the development of nociceptive dorsal horn circuits critical for mechanical and thermal pain processing.


Involvement of histamine in growth of mouse and rat tumors: antitumoral properties of monofluoromethylhistidine, an enzyme-activated irreversible inhibitor of histidine decarboxylase.
The present study suggests that newly synthesized histamine is involved in the development of some animal tumors (e.g., Lewis lung carcinoma in mice and Morris hepatoma in rats). A marked induction of histidine decarboxylase (HDC) and an increase in the histamine concentration were observed in the tumors approximately 1 week after inoculation, and there were parallel increases in ornithine decarboxylase activity and the concentrations of polyamines. The H2 receptor antagonist, cimetidine, significantly reduced tumor growth in the animal models while the H1 receptor antagonist, dexchlorpheniramine, had no effect, suggesting that histamine could act via H2 receptor sites. Extensive depletion of tumor histamine induced by local injection of Compound 48/80 did not result in a significant cytostatic effect. Monofluoromethylhistidine (MFMH), an enzyme-activated irreversible inhibitor of HDC, retarded the growth of hepatoma tissue culture cells grown in culture, and when infused s.c. at 60 mg/kg/day it greatly inhibited the development of tumors induced i.m. by hepatoma tissue culture cells in Buffalo rats. MFMH also had pronounced antitumoral effects on EMT6 sarcomas and Lewis lung carcinomas in mice, which were associated with inhibition of HDC and depletion of the histamine content of the tumors. These cytostatic effects were clearly enhanced when MFMH was combined in therapy with the specific ornithine decarboxylase inhibitor, DL-alpha-difluoromethylornithine. The antitumoral effects of the combination were associated with marked decreases in the tumor histamine and putrescine contents. It is proposed that nascent histamine, like newly synthesized putrescine and spermidine, plays a role in the rapid proliferation of animal tumors. Inhibition of HDC by essentially nontoxic drugs such as MFMH could represent a novel approach to the control of neoplastic growth.


Visual following and pattern discrimination of face-like stimuli by newborn infants.
Forty newborn infants, median age 9 minutes, turned their eyes and heads to follow a series of moving stimuli. Responsiveness was significantly greater to a proper face pattern than to either of two scrambled versions of the same stimulus or to a blank. The demonstration of such consistent response differences suggests that visual discriminations are being made at this early age. These results imply that organized visual perception is an unlearned capacity of the human organism. The preference for the proper face stimulus by infants who had not seen a real face prior to testing suggests that an unlearned or "evolved" responsiveness to faces may be present in human neonates.


Randomized, double blind placebo-controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS.
Oligomenorrhea and polycystic ovaries in women are one of the most important causes of the high incidence of ovulation failure. This is linked, perhaps, to insulin resistance and related metabolic features. A small number of reports show that myo-inositol improves ovarian function, but in these trials the quality of evidence supporting ovulation is suboptimal. Furthermore, few of them have been placebo-controlled. The aim of our study was to use a double-blind, placebo-controlled approach with detailed assessment of ovarian activity (two blood samples per week) to assess the validity of this therapeutic approach in this group of women. Of the 92 patients randomized, 47 received 400 mcg folic acid as placebo, and 45 received myo-inositol plus folic acid (4 g myo-inositol plus 400 mcg folic acid). The ovulation frequency assessed by the ratio of luteal phase weeks to observa-tion weeks was significantly (P < 0.01) higher in the treated group (25%) compared with the placebo (15%), and the time to first ovulation was significantly (P < 0.05) shorter [24.5 d; 95% confidence interval (CI), 18, 31; compared with 40.5 d; 95% CI, 27, 54]. The number of patients failing to ovulate during the placebo-treatment period was higher (P < 0.05) in the placebo group, and the majority of ovulations were characterized by normal progesterone concentrations in both groups. The effect of myo-inositol on follicular maturation was rapid, because the E2 circulating concentration increased over the first week of treatment only in the myo-inositol group. A significant increase in circulating high-density lipoprotein was observed only in the myo-inositol-treated group. Metabolic risk factor benefits of myo-inositol treatment were not observed in the morbidly obese subgroup of patients (body mass index > 37). After 14-wk myo-inositol or placebo therapy, no change in fasting glucose concentrations, fasting insulin, or insulin responses to glucose challenge was recorded. There was an inverse relationship between body mass and treatment efficacy. In fact a significant weight loss (and leptin reduction) (P < 0.01) was recorded in the myo-inositol group, whereas the placebo group actually increased weight (P < 0.05). These data support a beneficial effect of myo-inositol in women with oligomenorrhea and polycystic ovaries in improving ovarian function.


BEEHAVE: a systems model of honeybee colony dynamics and foraging to explore multifactorial causes of colony failure.
A notable increase in failure of managed European honeybee Apis mellifera L. colonies has been reported in various regions in recent years. Although the underlying causes remain unclear, it is likely that a combination of stressors act together, particularly varroa mites and other pathogens, forage availability and potentially pesticides. It is experimentally challenging to address causality at the colony scale when multiple factors interact. In silico experiments offer a fast and cost-effective way to begin to address these challenges and inform experiments. However, none of the published bee models combine colony dynamics with foraging patterns and varroa dynamics.We have developed a honeybee model, BEEHAVE, which integrates colony dynamics, population dynamics of the varroa mite, epidemiology of varroa-transmitted viruses and allows foragers in an agent-based foraging model to collect food from a representation of a spatially explicit landscape.We describe the model, which is freely available online (www.beehave-model.net). Extensive sensitivity analyses and tests illustrate the model's robustness and realism. Simulation experiments with various combinations of stressors demonstrate, in simplified landscape settings, the model's potential: predicting colony dynamics and potential losses with and without varroa mites under different foraging conditions and under pesticide application. We also show how mitigation measures can be tested.Synthesis and applications. BEEHAVE offers a valuable tool for researchers to design and focus field experiments, for regulators to explore the relative importance of stressors to devise management and policy advice and for beekeepers to understand and predict varroa dynamics and effects of management interventions. We expect that scientists and stakeholders will find a variety of applications for BEEHAVE, stimulating further model development and the possible inclusion of other stressors of potential importance to honeybee colony dynamics.


Multilayers of hydrogels loaded with microparticles: a fast and simple approach for microarray manufacturing.
We present a novel and simple approach towards the creation of arrays of biomolecules for the multiplexed detection of biological interactions. Microarrays were obtained by cutting stacked layers of biofunctionalized polystyrene particle layers embedded in a permeable agarose matrix. Microparticles were therefore the vehicles for biorecognition. The three-dimensional constructs were obtained by consecutive dipping steps in a pre-gel solution. Our strategy enables the rapid manufacturing of a large number of array copies in a flexible manner and without any specialized instrumentation. Model binding assays for the detection of rabbit and mouse IgG were performed as a proof of concept using a fluorescence microscope for read-out. The limits of detection were in the low picomolar range for the sandwich assay while 1 IgG out of 50,000 background proteins could be detected in a reverse phase assay. Thus, without any assay optimization, sensitivities comparable to the ones usually observed for standard fluorescence-based assays were achieved with the particle/hydrogel array.


Radium isotope ((223)Ra, (224)Ra, (226)Ra and (228)Ra) distribution near Brazil's largest port, Paranaguá Bay, Brazil.
This work investigates the (223)Ra, (224)Ra, (226)Ra and (228)Ra isotope distribution in river, estuarine waters and sediments of the Paranaguá Estuarine Complex (PEC). The stratification of the Ra isotopes along water columns indicate differing natural sources. In sediments, the radium isotope activities was inversely proportional to the particle size. The highest concentrations of (223)Ra, (224)Ra, (226)Ra and (228)Ra in the water column were found in the bottom more saline waters and towards the inner of the estuary. These relatively high concentrations towards the bottom of the estuary may be attributed to the influence of tidally driven groundwater source and desorption from particles at the maximum turbidity zone. The apparent river water ages from the radium isotope ratios, (223)Ra/(224)Ra and (223)Ra/(228)Ra, indicate that the principal rivers that flow into the estuary have residence times from between 6 and 11days.


The golden gene (SLC24A5) differentiates US sub-populations within the ethnically admixed Y-SNP haplogroups.
Y-SNPs are currently being investigated for their potential to predict the ethnogeographic origin of the donor of a crime scene sample. Unfortunately, due to the presence of genetically admixed individuals within ethnic sub-populations within a particular haplogroup (hg), it is sometimes difficult to predict the ethnogeographic ancestry of an individual using only Y-SNPs. In the present work we determine the feasibility of using a combination of the golden pigmentation gene (SLC24A5) SNP and recently described high resolution Y-SNP markers to distinguish some of the different ethnic groups within particular Y-SNP hgs. Four hundred twenty-four individuals (128 African, 206 European, 50 Hispanic/Latin, 20 Pakistan, 20 E.Asian/Indian) were typed for a SNP within the golden gene. The Y-SNP hg was determined for all males and it was found that many of the European derived hg possessed a significant amount of ethnic admixture, with R1b3 having the most. We show the use of the golden gene, in combination with more informative Y-SNPs (U152, U106, and M222) and those that define the major hg, can differentiate between most of the African vs. European and African vs. E. Asian members of these heterogeneous populations.


Functionalized gold and persistent luminescence nanoparticle-based ratiometric absorption and TR-FRET nanoplatform for high-throughput sequential detection of l-cysteine and insulin.
In vitro diagnostic is a crucial component of healthcare systems for early diagnosis of diseases and follow-up therapy, which generally makes clinical diagnosis faster, easier, and painless for patients. Herein, we report a dual-signaling nanoplatform for ratiometric absorption and time-resolved fluorescence resonance energy transfer based on l-cysteine-mediated aggregated gold nanoparticles and long afterglow nature of persistent luminescence nanoparticles. With this nanoplatform, we have achieved high-throughput sequential detection of l-cysteine and insulin in human serum without matrix interference. The proposed nanoplatform shows excellent linearity and precision for the determination of l-cysteine in the range of 10 nM to 5.5 μM with the limit of detection (LOD) of 2.2 nM and for the detection of insulin in the range of 12 pM to 3.44 nM with LOD of 2.06 pM. The developed dual-signaling nanoplatform has been successfully applied for the sequential determination of l-cysteine and insulin in human serum.


A leptin derived 30-amino-acid peptide modified pegylated poly-L-lysine dendrigraft for brain targeted gene delivery.
The blood-brain barrier is the major obstacle that prevents diagnostic and therapeutic drugs being delivered to the central nervous systems in order to exert their effects. Specific ligand-receptor binding mediated endocytosis is one of the possible strategies to cross this barrier. A 30-amino-acid peptide (leptin30) derived from an endogenic hormone-leptin is exploited as brain-targeting ligand as it is reported to possess the same brain accumulation efficiency after intravenous injection. Dendrigraft poly-L-lysine (DGL) is used as non-viral gene vector in this study. DGL-PEG-Leptin30 was complexed with plasmid DNA yielding nanoparticles (NPs). The cellular uptake characteristic and mechanism were explored in brain capillary endothelial cells (BCECs) which express leptin receptors. Furthermore, brain parenchyma microglia cells such as BV-2 cells expressing leptin receptors could promote ligand-receptor mediated endocytosis leading to enhanced gene transfection ability of DGL-PEG-Leptin30/DNA NPs. The targeted NPs were proved to be transported across in vitro BBB model effectively and accumulate more in brains after i.v. resulting in a relatively high gene transfection efficiency both in vitro and in vivo. Besides, the NPs showed low cytotoxicity after in vitro transfection. Thus, DGL-PEG-Leptin30 provides a safe and noninvasive approach for the delivery of gene across the blood-brain barrier.


Roles of innervation in developing and regenerating orofacial tissues.
The head is innervated by 12 cranial nerves (I-XII) that regulate its sensory and motor functions. Cranial nerves are composed of sensory, motor, or mixed neuronal populations. Sensory neurons perceive generally somatic sensations such as pressure, pain, and temperature. These neurons are also involved in smell, vision, taste, and hearing. Motor neurons ensure the motility of all muscles and glands. Innervation plays an essential role in the development of the various orofacial structures during embryogenesis. Hypoplastic cranial nerves often lead to abnormal development of their target organs and tissues. For example, Möbius syndrome is a congenital disease characterized by defective innervation (i.e., abducens (VI) and facial (VII) nerves), deafness, tooth anomalies, and cleft palate. Hence, it is obvious that the peripheral nervous system is needed for both development and function of orofacial structures. Nerves have a limited capacity to regenerate. However, neural stem cells, which could be used as sources for neural tissue maintenance and repair, have been found in adult neuronal tissues. Similarly, various adult stem cell populations have been isolated from almost all organs of the human body. Stem cells are tightly regulated by their microenvironment, the stem cell niche. Deregulation of adult stem cell behavior results in the development of pathologies such as tumor formation or early tissue senescence. It is thus essential to understand the factors that regulate the functions and maintenance of stem cells. Yet, the potential importance of innervation in the regulation of stem cells and/or their niches in most organs and tissues is largely unexplored. This review focuses on the potential role of innervation in the development and homeostasis of orofacial structures and discusses its possible association with stem cell populations during tissue repair.


Isolation of three Mycobacterium ulcerans strains resistant to rifampin after experimental chemotherapy of mice.
By use of a murine model for Buruli ulcer, Mycobacterium ulcerans was found to be susceptible to rifampin, with the MIC being 0.5 to 1 micro g/ml. Three mutants were isolated after rifampin monotherapy. Two were resistant to rifampin at 8 micro g/ml, and one was resistant to rifampin at 32 micro g/ml. The mutants harbored Ser416Phe mutations and His420Tyr mutations in the rpoB gene, and these mutations have also been found to be responsible for rifampin resistance in the leprosy and tubercle bacilli. The results indicate that while rifampin may be active against M. ulcerans, it should never be used as monotherapy in humans.


Oxidative status--age- and circadian variations?--a study in leukocytes/plasma.
In the present paper the circadian variation and age differences in human leukocyte reactive oxygen species (ROS) levels and plasma total antioxidant status were studied. Different ROS levels could influence disease during ageing and at different times of the day/night. Unstimulated and stimulated (12-O-tetradecanoyl-phorbol-13-acetate (TPA) blood samples were analysed by flow cytometry using dihydroethidium (DHE) and dihydrorhodamine 123 (DHR) as probes. 60 healthy individuals were divided into five equal groups ((I) 1-2 days post partum, (II) 20 +/- 2 years, (III) 40 +/- 2 years, (IV) 60 +/- 2 years and (V) 80 +/- 2 years) and 6 healthy volunteers were followed with blood samples at 3 hour intervals for 24 hours. We observed a significant peak of ROS levels in both monocytes and granulocytes at 6 pm and 3 am using DHE as probe. DHR showed in principle the same pattern. The monocytes (unstimulated and stimulated) and unstimulated granulocytes of the newborn group showed higher ROS values than all the other groups, whereas the groups of adults did not differ from each other. The plasma total antioxidant status was significantly higher in the newborn group and showed no circadian variation. The present data show that there is a circadian variation of ROS production in leukocytes that might possibly influence the occurrence of cardiovascular incidents like myocardial infarction. No increase in ROS production was found in healthy elderly compared to younger individuals. The increased ROS levels and antioxidant status of newborns might influence neonate immunity and play a part in cell signalling and development.


IgG4 autoantibodies against muscle-specific kinase undergo Fab-arm exchange in myasthenia gravis patients.
Autoimmunity mediated by IgG4 subclass autoantibodies is an expanding field of research. Due to their structural characteristics a key feature of IgG4 antibodies is the ability to exchange Fab-arms with other, unrelated, IgG4 molecules, making the IgG4 molecule potentially monovalent for the specific antigen. However, whether those disease-associated antigen-specific IgG4 are mono- or divalent for their antigens is unknown. Myasthenia gravis (MG) with antibodies to muscle specific kinase (MuSK-MG) is a well-recognized disease in which the predominant pathogenic IgG4 antibody binds to extracellular epitopes on MuSK at the neuromuscular junction; this inhibits a pathway that clusters the acetylcholine (neurotransmitter) receptors and leads to failure of neuromuscular transmission. In vitro Fab-arm exchange-inducing conditions were applied to MuSK antibodies in sera, purified IgG4 and IgG1-3 sub-fractions. Solid-phase cross-linking assays were established to determine the extent of pre-existing and inducible Fab-arm exchange. Functional effects of the resulting populations of IgG4 antibodies were determined by measuring inhibition of agrin-induced AChR clustering in C2C12 cells. To confirm the results, κ/κ, λ/λ and hybrid κ/λ IgG4s were isolated and tested for MuSK antibodies. At least fifty percent of patients had IgG4, but not IgG1-3, MuSK antibodies that could undergo Fab-arm exchange in vitro under reducing conditions. Also MuSK antibodies were found in vivo that were divalent (monospecific for MuSK). Fab-arm exchange with normal human IgG4 did not prevent the inhibitory effect of serum derived MuSK antibodies on AChR clustering in C2C12 mouse myotubes. The results suggest that a considerable proportion of MuSK IgG4 could already be Fab-arm exchanged in vivo. This was confirmed by isolating endogenous IgG4 MuSK antibodies containing both κ and λ light chains, i.e. hybrid IgG4 molecules. These new findings demonstrate that Fab-arm exchanged antibodies are pathogenic.


Losing control: assaultive behavior as a predictor of impulse control disorders in young adults.
Assaultive behaviors are common among young people and have been associated with a range of other unhealthy, impulsive behaviors such as substance use and problem gambling. This study sought to determine the predictive ability of single assaultive incidents for impulse control disorders, an association that has yet to be examined, especially in young adults. The authors conducted a university-wide email survey in the spring of 2011 on 6000 university students. The survey examined assaultive behavior and associated mental health variables (using a clinically validated screening instrument, the Minnesota Impulsive Disorders Interview), stress and mood states, and psychosocial functioning. The rate of response was 35.1% (n=2108). 109 (5.9%) participants reported that they had assaulted another person or destroyed property at some time in their lives. Compared with respondents without lifetime assaultive behavior, those with a history of assaultive or destructive behavior reported more depressive symptoms, more stress, and higher rates of a range of impulse control disorders (intermittent explosive disorder, compulsive sexual behavior, compulsive buying, and skin picking disorder). Assaultive behavior appears fairly common among college students and is associated with symptoms of depression and impulse control disorders. Significant distress and diminished behavioral control suggest that assaultive behaviors may often be associated with significant morbidity. Additional research is needed to develop specific prevention and treatment strategies for young adults attending college who report problems with assaultive behaviors.


Brain tumour diagnostics using a DNA methylation-based classifier as a diagnostic support tool.
Methylation profiling (MP) is increasingly incorporated in the diagnostic process of central nervous system (CNS) tumours at our centres in The Netherlands and Scandinavia. We aimed to identify the benefits and challenges of MP as a support tool for CNS tumour diagnostics. About 502 CNS tumour samples were analysed using (850 k) MP. Profiles were matched with the DKFZ/Heidelberg CNS Tumour Classifier. For each case, the final pathological diagnosis was compared to the diagnosis before MP. In 54.4% (273/502) of all analysed cases, the suggested methylation class (calibrated score ≥0.9) corresponded with the initial pathological diagnosis. The diagnosis of 24.5% of these cases (67/273) was more refined after incorporation of the MP result. In 9.8% of cases (49/502), the MP result led to a new diagnosis, resulting in an altered WHO grade in 71.4% of these cases (35/49). In 1% of cases (5/502), the suggested class based on MP was initially disregarded/interpreted as misleading, but in retrospect, the MP result predicted the right diagnosis for three of these cases. In six cases, the suggested class was interpreted as 'discrepant but noncontributory'. The remaining 33.7% of cases (169/502) had a calibrated score <0.9, including 7.8% (39/502) for which no class indication was given at all (calibrated score <0.3). MP is a powerful tool to confirm and fine-tune the pathological diagnosis of CNS tumours, and to avoid misdiagnoses. However, it is crucial to interpret the results in the context of clinical, radiological, histopathological and other molecular information.


Applied physiology of tennis performance.
Competitive tennis play requires a combination of the major physiological variables; however, the specifics of these variables have yet to be determined appropriately. General strength and flexibility training have been suggested as being beneficial for performance and injury prevention, yet specific guidelines are lacking. This paper provides a review of specific studies that relate to competitive tennis, and highlights the need for tennis-specific training as opposed to generalised physical training. It identifies specific studies that support the premise that tennis has physiological requirements which need to be understood when designing training and research programmes.


Identification of putative active site residues of ACAT enzymes.
In this report, we sought to determine the putative active site residues of ACAT enzymes. For experimental purposes, a particular region of the C-terminal end of the ACAT protein was selected as the putative active site domain due to its high degree of sequence conservation from yeast to humans. Because ACAT enzymes have an intrinsic thioesterase activity, we hypothesized that by analogy with the thioesterase domain of fatty acid synthase, the active site of ACAT enzymes may comprise a catalytic triad of ser-his-asp (S-H-D) amino acid residues. Mutagenesis studies revealed that in ACAT1, S456, H460, and D400 were essential for activity. In ACAT2, H438 was required for enzymatic activity. However, mutation of D378 destabilized the enzyme. Surprisingly, we were unable to identify any S mutations of ACAT2 that abolished catalytic activity. Moreover, ACAT2 was insensitive to serine-modifying reagents, whereas ACAT1 was not. Further studies indicated that tyrosine residues may be important for ACAT activity. Mutational analysis showed that the tyrosine residue of the highly conserved FYXDWWN motif was important for ACAT activity. Furthermore, Y518 was necessary for ACAT1 activity, whereas the analogous residue in ACAT2, Y496, was not. The available data suggest that the amino acid requirement for ACAT activity may be different for the two ACAT isozymes.


Elevated oxidative membrane damage associated with genetic modifiers of Lyst-mutant phenotypes.
LYST is a large cytosolic protein that influences the biogenesis of lysosome-related organelles, and mutation of the encoding gene, LYST, can cause Chediak-Higashi syndrome. Recently, Lyst-mutant mice were recognized to also exhibit an iris disease resembling exfoliation syndrome, a common cause of glaucoma in humans. Here, Lyst-mutant iris phenotypes were used in a search for genes that influence Lyst pathways. In a candidate gene-driven approach, albino Lyst-mutant mice homozygous for a mutation in Tyr, whose product is key to melanin synthesis within melanosomes, exhibited complete rescue of Lyst-mutant iris phenotypes. In a genetic background-driven approach using a DBA/2J strain of congenic mice, an interval containing Tyrp1 enhanced Lyst-dependent iris phenotypes. Thus, both experimental approaches implicated the melanosome, an organelle that is a potential source of oxidative stress, as contributing to the disease phenotype. Confirming an association with oxidative damage, Lyst mutation resulted in genetic context-sensitive changes in iris lipid hydroperoxide levels, being lowest in albino and highest in DBA/2J mice. Surprisingly, the DBA/2J genetic background also exposed a late-onset neurodegenerative phenotype involving cerebellar Purkinje-cell degeneration. These results identify an association between oxidative damage to lipid membranes and the severity of Lyst-mutant phenotypes, revealing a new mechanism that contributes to pathophysiology involving LYST.


Association between hypertension and periodontitis: possible mechanisms.
This review is to examine the current literatures on the relationship between periodontitis and hypertension as well as to explore the possible biological pathways underlying the linkage between these health conditions. Hypertension is one of the major risk factors for cardiovascular diseases. Oxidative stress and endothelial dysfunction are among the critical components in the development of hypertension. Inflammation has received much attention recently and may contribute to a pivotal role in hypertension. Periodontitis, a chronic low-grade inflammation of gingival tissue, has been linked to endothelial dysfunction, with blood pressure elevation and increased mortality risk in hypertensive patients. Inflammatory biomarkers are increased in hypertensive patients with periodontitis. Over the years, various researches have been performed to evaluate the involvement of periodontitis in the initiation and progression of hypertension. Many cross-sectional studies documented an association between hypertension and periodontitis. However, more well-designed prospective population trials need to be carried out to ascertain the role of periodontitis in hypertension.


ABCE1 is a highly conserved RNA silencing suppressor.
ATP-binding cassette sub-family E member 1 (ABCE1) is a highly conserved protein among eukaryotes and archaea. Recent studies have identified ABCE1 as a ribosome-recycling factor important for translation termination in mammalian cells, yeast and also archaea. Here we report another conserved function of ABCE1. We have previously described AtRLI2, the homolog of ABCE1 in the plant Arabidopsis thaliana, as an endogenous suppressor of RNA silencing. In this study we show that this function is conserved: human ABCE1 is able to suppress RNA silencing in Nicotiana benthamiana plants, in mammalian HEK293 cells and in the worm Caenorhabditis elegans. Using co-immunoprecipitation and mass spectrometry, we found a number of potential ABCE1-interacting proteins that might support its function as an endogenous suppressor of RNA interference. The interactor candidates are associated with epigenetic regulation, transcription, RNA processing and mRNA surveillance. In addition, one of the identified proteins is translin, which together with its binding partner TRAX supports RNA interference.


Texas Sour Orange Juice Used in Scaffolds for Tissue Engineering.
Fine fibers of polyhydroxybutyrate (PHB), a biopolymer, were developed via a centrifugal spinning technique. The developed fibers have an average diameter of 1.8 µm. Texas sour orange juice (SOJ) was applied as a natural antibacterial agent and infiltrated within the fibrous membranes. The antibacterial activity against common Gram-positive and Gram-negative bacteria (Staphylococcus aureus and Escherichia coli, respectively) was evaluated as well as cell adhesion and viability. The PHB/SOJ scaffolds showed antibacterial activity of up to 152% and 71% against S. aureus and E. coli, respectively. The cell studies revealed a suitable environment for cell growth and cell attachment. The outcome of this study opens up new opportunities for fabrication of fibrous materials for biomedical applications having multifunctional properties while using natural agents.


Improvement in outcomes after implantation of a novel polyurethane meniscal scaffold for the treatment of medial meniscus deficiency.
Meniscal injury resulting in segmental loss of meniscal tissue is a major risk factor for the development of osteoarthritis. Tissue engineering strategies have provided scaffolds for meniscal regeneration in order to establish a treatment option for patients with limited opportunities for meniscal reconstruction. The purpose of this study was to assess the clinical and magnetic resonance imaging (MRI) results 2 years after implantation of a polyurethane scaffold for chronic segmental medial meniscus deficiency following partial medial meniscectomy. Eighteen patients were treated with arthroscopic implantation of an ActiFit(®) (Orteq Sports Medicine) polyurethane meniscal scaffold for meniscus deficiency of the medial meniscus. Patients were followed up at 6, 12, and 24 months. Clinical outcome was assessed using patient-reported outcome scores (KOOS, KSS, UCLA activity scale, VAS for pain). Radiological outcome was assessed using MRI at 6, 12, and 24 months by evaluating scaffold morphology, scaffold integration, and additional joint injury, as well as joint inflammation. Eighteen patients with a median age of 32.5 years (range 17-49) were enrolled. Statistically significant improvements were present in all patients, but one at 2 years compared to baseline in all categories. Complete resorption of the scaffold occurred in one patient representing a failure to treatment. MRI showed abnormal signal intensity of the scaffold when compared to residual meniscal tissue but without synovitis or joint inflammation. Extrusion of the scaffold was present in four patients. No correlation between scaffold extrusion and clinical outcome was observed. Arthroscopic implantation of a polyurethane meniscal scaffold in patients with chronic segmental medial meniscus deficiency is not only a safe procedure but leads to good clinical results at a 2-year follow-up. Scaffold extrusion did not appear to affect clinical outcome. IV.


Excited-state enhancement of third-order optical nonlinearities: photodynamics and characterization.
Based on the simplified five-level rate-equation theory, we investigate the hybrid third-order optical nonlinear processes which combine the instantaneous nonlinearity and the one-photon absorption induced excited-state nonlinearity. We obtain the analytical third-order nonlinear absorption and refraction coefficients originating from the singlet and triplet excited-state effects. We explore the photodynamic process and give the corresponding level diagram in the nanosecond, picosecond, and femtosecond regimes. We develop the pulse-duration-dependent Z-scan theory for characterizing the simultaneous instantaneous nonlinearity and cumulative effect of the excited-state nonlinearity. We also demonstrate the validity of the presented theory to analyze the experimental results.


Model for Identifying Individuals at Risk for Esophageal Adenocarcinoma.
The prognosis for most patients with esophageal adenocarcinoma (EAC) is poor because they present with advanced disease. Models developed to identify patients at risk for EAC and increase early detection have been developed based on data from case-control studies. We analyzed data from a prospective study to identify factors available to clinicians that identify individuals with a high absolute risk of EAC. We collected data from 355,034 individuals (all older than 50 years) without a prior history of cancer enrolled in the UK Biobank prospective cohort study from 2006 through 2010; clinical data were collected through September 2014. We identified demographic, lifestyle, and medical factors, measured at baseline, that associated with development of EAC within 5 years using logistic regression analysis. We used these data to create a model to identify individuals at risk for EAC. Model performance was assessed using area under the receiver operating characteristics curve (AUROC), sensitivity, and specificity analyses. Within up to 5 years of follow up, 220 individuals developed EAC. Age, sex, smoking, body mass index, and history of esophageal conditions or treatments identified individuals who developed EAC (AUROC, 0.80; 95% CI, 0.77-0.82). We used these factors to develop a scoring system and identified a point cut off that 104,723 individuals (29.5%), including 170 of the 220 cases with EAC, were above. The scoring system identified individuals who developed EAC with 77.4% sensitivity and 70.5% specificity. The 5-year risk of EAC was 0.16% for individuals with scores above the threshold and 0.02% for individuals with scores below the threshold. We combined data on several well-established risk factors that are available to clinicians to develop a system to identify individuals with a higher absolute risk of EAC within 5 years. Studies are needed to evaluate the utility of these factors in a multi-stage, triaged, screening program.


The influence of mitigation on sage-grouse habitat selection within an energy development field.
Growing global energy demands ensure the continued growth of energy development. Energy development in wildlife areas can significantly impact wildlife populations. Efforts to mitigate development impacts to wildlife are on-going, but the effectiveness of such efforts is seldom monitored or assessed. Greater sage-grouse (Centrocercus urophasianus) are sensitive to energy development and likely serve as an effective umbrella species for other sagebrush-steppe obligate wildlife. We assessed the response of birds within an energy development area before and after the implementation of mitigation action. Additionally, we quantified changes in habitat distribution and abundance in pre- and post-mitigation landscapes. Sage-grouse avoidance of energy development at large spatial scales is well documented. We limited our research to directly within an energy development field in order to assess the influence of mitigation in close proximity to energy infrastructure. We used nest-location data (n = 488) within an energy development field to develop habitat selection models using logistic regression on data from 4 years of research prior to mitigation and for 4 years following the implementation of extensive mitigation efforts (e.g., decreased activity, buried powerlines). The post-mitigation habitat selection models indicated less avoidance of wells (well density β = 0.18 ± 0.08) than the pre-mitigation models (well density β = -0.09 ± 0.11). However, birds still avoided areas of high well density and nests were not found in areas with greater than 4 wells per km2 and the majority of nests (63%) were located in areas with ≤ 1 well per km2. Several other model coefficients differed between the two time periods and indicated stronger selection for sagebrush (pre-mitigation β = 0.30 ± 0.09; post-mitigation β = 0.82 ± 0.08) and less avoidance of rugged terrain (pre-mitigation β = -0.35 ± 0.12; post-mitigation β = -0.05 ± 0.09). Mitigation efforts implemented may be responsible for the measurable improvement in sage-grouse nesting habitats within the development area. However, we cannot reject alternative hypotheses concerning the influence of population density and intraspecific competition. Additionally, we were unable to assess the actual fitness consequences of mitigation or the source-sink dynamics of the habitats. We compared the pre-mitigation and post-mitigation models predicted as maps with habitats ranked from low to high relative probability of use (equal-area bins: 1 - 5). We found more improvement in habitat rank between the two time periods around mitigated wells compared to non-mitigated wells. Informed mitigation within energy development fields could help improve habitats within the field. We recommend that any mitigation effort include well-informed plans to monitor the effectiveness of the implemented mitigation actions that assess both habitat use and relevant fitness parameters.


The origins of the Acheulean: past and present perspectives on a major transition in human evolution.
The emergence of the Acheulean from the earlier Oldowan constitutes a major transition in human evolution, the theme of this special issue. This paper discusses the evidence for the origins of the Acheulean, a cornerstone in the history of human technology, from two perspectives; firstly, a review of the history of investigations on Acheulean research is presented. This approach introduces the evolution of theories throughout the development of the discipline, and reviews the way in which cumulative knowledge led to the prevalent explanatory framework for the emergence of the Acheulean. The second part presents the current state of the art in Acheulean origins research, and reviews the hard evidence for the appearance of this technology in Africa around 1.7 Ma, and its significance for the evolutionary history of Homo erectusThis article is part of the themed issue 'Major transitions in human evolution'.


Hiatal hernia uptake of iodine-131 mimicking mediastinal metastasis of papillary thyroid carcinoma.
There are a few case reports of hiatal hernia demonstrating thoracic uptake on I-131 scintigraphy. In this case, high thyroglobulin levels in combination with misinterpretation of I-131 uptake in the mediastinum, leaded to mismanagement of the patient. Here we present a case of focal I-131 uptake within a hiatal hernia initially mimicking an isolated mediastinal metastasis. There are many potential causes of false-positive I-131 scan result. In this case, adjunctive chest computed tomography and gastroesophageal barium study helped to elucidate the true nature of this I-131 uptake. False-positive findings may be caused by a wide variety of nonthyroidal carcinomas, which can concentrate radioiodine or from skin contamination. Several organs, such as the gastric, salivary glands, renal cyst, pericardial effusion, and ovarian can accumulate I-131. It should be borne in mind as a potential source of false-positive whole-body I-131 imaging.


Cardiovascular disease in non-classic Pompe disease: A systematic review.
Pompe disease is a rare inherited metabolic and neuromuscular disorder, presenting as a spectrum, with the classic infantile form on one end and the more slowly progressive non-classic form on the other end. While being a hallmark in classic infantile Pompe disease, cardiac involvement in non-classic Pompe disease seems rare. Vascular abnormalities, such as aneurysms and arterial dolichoectasia, likely caused by glycogen accumulation in arterial walls, have been reported in non-classic Pompe patients. With this first systematic review on cardiovascular disease in non-classic Pompe disease, we aim to gain insight in the prevalence and etiology of cardiovascular disease in these patients. Forty-eight studies (eight case-control studies, 15 cohort studies and 25 case reports/series) were included. Fourteen studies reported cardiac findings, 25 studies described vascular findings, and nine studies reported both cardiac and vascular findings. Severe cardiac involvement in non-classic Pompe disease patients has rarely been reported, particularly in adult-onset patients carrying the common IVS1 mutation. There are indications that intracranial dolichoectasia and aneurysms are more prevalent in non-classic Pompe patients compared to the general population. To further investigate the prevalence of cardiovascular disease in non-classic Pompe patients, larger case-control studies that also study established cardiovascular risk factors should be conducted.


Childhood Victimization, Recent Injustice, Anger, and Forgiveness in a Sample of Imprisoned Male Offenders.
The links between childhood victimization, subsequent emotional dysregulation, and insufficient coping skills have been repeatedly documented in the scientific literature. However, there is a gap in the literature regarding the role of forgiveness as a coping strategy and relationships between offense-specific hurt, chronic anger, and early victimization. The goals of our study were (a) to explore how offenders cope with recent unjust treatment, and test the links between type of injustice, hurt experienced due to injustice, and use of forgiveness; (b) to test the links between childhood victimization, hurt, and chronic anger; and (c) to assess the mediating role of chronic anger in relation to hurt and forgiveness. The results reveal that multiplicity and severity of victimization exposure in the prison sample are positively associated with chronic anger, but not with hurt. The type of injustice affects the level of hurt and forgiveness, while chronic anger mediates the link between hurt and forgiveness. To improve coping and promote forgiving, offenders should be helped to identify everyday sources of stress and learn to express vulnerable feelings beneath anger.


Mitochondrial protective effect of neferine through the modulation of nuclear factor erythroid 2-related factor 2 signalling in ischaemic stroke.
Ischaemic stroke is a leading cause of death and long-term disability. Promising neuroprotective compounds are urgently needed to overcome clinical therapeutic limitations. Neuroprotective agents are limited to single-target agents, which further limit their clinical effectiveness. Due to the brain's particular energy requirements, the energy micro-environment, centred in mitochondria, is a new research hotspot in the complex pathology of ischaemic stroke. Here, we studied the effects of neferine (Nef), a bis-benzylisoquinoline alkaloid extracted from the seed embryo of Nelumbo nucifera Gaertn, on ischaemic stroke and its underlying mitochondrial protective mechanisms. Rats with permanent middle cerebral artery occlusion (pMCAO)-induced focal cerebral ischaemia and tert-butyl hydroperoxide (t-BHP)-injured PC12 cells were used to investigate the neuroprotective effects of Nef, particularly with regard to energy micro-environment regulation by mitochondria and its mechanism in vivo and in vitro. Nef protected t-BHP-injured PC12 cells in vitro and ameliorated neurological score, infarct volume, regional cerebral blood flow, cerebral microstructure and oxidant-related enzyme deficits in pMCAO rats in vivo. Nef also prevented mitochondrial dysfunction both in vivo and in vitro. The underlying mechanism of the mitochondrial protective effect of Nef might be attributed to the increased translocation of Nrf2 to the nucleus. Furthermore, the translocation of Nrf2 to nucleus was also decreased by sequestosome 1 (p62) knockdown. Our results demonstrated that Nef might have therapeutic potential for ischaemic stroke and may exert its protective role through mitochondrial protection. This protection might be attributed to the modulation of Nrf2 signalling.


Scan Order in Gibbs Sampling: Models in Which it Matters and Bounds on How Much.
Gibbs sampling is a Markov Chain Monte Carlo sampling technique that iteratively samples variables from their conditional distributions. There are two common scan orders for the variables: random scan and systematic scan. Due to the benefits of locality in hardware, systematic scan is commonly used, even though most statistical guarantees are only for random scan. While it has been conjectured that the mixing times of random scan and systematic scan do not differ by more than a logarithmic factor, we show by counterexample that this is not the case, and we prove that that the mixing times do not differ by more than a polynomial factor under mild conditions. To prove these relative bounds, we introduce a method of augmenting the state space to study systematic scan using conductance.


Growth factors and proto-oncogenes in early mouse embryogenesis and tumorigenesis.
Growth factors and proto-oncogenes play an important role in the regulation of embryonic growth and differentiation as well as in tumorigenesis. Insulin and insulin-like growth factor I (IGF I) are secreted by embryonic tissues during the prepancreatic stage of mouse development. Measureable amounts of these factors were found in 8- to 12-day-old embryos. Embryonic cells derived from 8- to 10-day-old embryos secrete insulin and IGF I in serum-free medium. Relatively high levels of c-myc, c-fos and c-H-ras oncoproteins were also detected in 8- to 12-day-old embryos. Insulin and IGF I, when added to the culture of embryonic cells, stimulate their proliferation. Similar results were obtained in some animal or human tumors. Murine myeloid leukemias and melanoma B 16 secrete a substance immunologically cross reactive with insulin (SICRI) both in vivo and in serum-free media. In culture, the DNA synthesis rate per leukemic or melanoma cell is proportional to cell density and is reduced by antiinsulin serum in case of leukemic cells. Human hemangiosarcoma secrete IGF I, which also plays a role as an autocrine factor. Purified IGF I efficiently induce c-myc and c-fos mRNA, which is among the earliest events following growth factor stimulation, leading to mitosis. These results lead us to the conclusion that IGF I and insulin together with oncoproteins stimulate the growth of embryonic and tumor cells, which is indirect evidence for a paracrine (or autocrine) type of action.


Lymphatic imaging in experimental filariasis using magnetic resonance.
To evaluate acquired lymphatic abnormalities caused by filariasis, the authors examined the peripheral lymphatic system in normal ferrets and those chronically infected with Brugia malayi using magnetic resonance imaging (MRI). The findings were compared with previously obtained lymphangioscintigraphic (LAS) images in ferrets both with and without experimental filariasis. Fifteen ferrets (11 infected with B. malayi and four noninfected controls) underwent whole body coronal MRI using a quadrature transmission-receive head coil at 0.5 Tesla operating at a resonant frequency of 21.5 mHz for protons with a 25-cm field of view. In contrast to normal animals, infected ferrets showed dilated hindlimb dermal lymphatic collaterals, enlarged high-signal intensity groin lymph nodes with punctate low-signal intensity centers and separate low-signal intensity spots with irregular thin channels, suggestive of nests of viable adult nematodes within tortuous lymphatics and nodes. MRI correlated with the LAS findings, and the interpretations were supported by light, scanning electron, and video microscopy. T2-weighted MRI in conjunction with LAS accurately depicts the peripheral lymphatic system in filarial-infected ferrets. These two modalities are useful complementary techniques to examine disorders characterized by lymphatic insufficiency.


Heritability of testosterone levels in 12-year-old twins and its relation to pubertal development.
The aim of this study was to estimate the heritability of variation in testosterone levels in 12-year-old children, and to explore the overlap in genetic and environmental influences on circulating testosterone levels and androgen-dependent pubertal development. Midday salivary testosterone samples were collected on 2 consecutive days in a sample of 183 unselected twin pairs. Androgen-induced pubertal development was assessed using self-report Tanner scales of pubic hair development (boys and girls) and genital development (boys). A significant contribution of genetic effects to the variance in testosterone levels was found. Heritability was approximately 50% in both boys and girls. The remaining proportion of the variance in testosterone levels could be explained by nonshared environmental influences. The relatively high correlation between testosterone levels of opposite-sex dizygotic twins suggests that sex differences in genes influencing variation in testosterone levels have not yet developed in pre- and early puberty. Variance in pubertal development was explained by a large genetic component, moderate shared environmental influences, and a small nonshared environmental effect. Testosterone levels correlated moderately (r = .31) with pubertal development; the covariance between testosterone levels and pubertal development was entirely accounted for by genetic influences.


Seasonal phenology of Aphis glycines (Hemiptera: Aphididae) and other aphid species in cultivated bean and noncrop habitats in Wisconsin.
The occurrence of aphid-transmitted viruses in agricultural crops of the Midwest and northeastern United States has become more frequent since the arrival and establishment of the soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae). A. glycines is a competent vector of plant viruses and may be responsible for recent virus epidemics in Wisconsin snap bean, Phaseolus vulgaris L., fields. To determine whether vegetation surrounding crop fields could serve as sources of virus inocula, we examined the settling activity ofA. glycines and other aphid species in agricultural crops and noncrop field margins adjacent to snap bean fields. Noncrop field margins were made up of numerous virus-susceptible plant species within 10 m from snap bean field edges. During summers 2006 and 2007, horizontal pan traps were placed in commercial soybean [Glycine max (L.) Merr.], snap bean, and surrounding field margins to characterize aphid flight activity patterns in the different habitat types. Alate abundance and peak occurrence across years varied between crop and noncrop field margins and differed among patches of plants in field margins. Overall aphid activity peaked late in the season (21 August in 2006 and 28 July in 2007); with the majority (52%) of total aphids trapped in all habitats being A. glycines. Susceptibility to viral infection and confirmed visitation of A. glycines to these forage plants suggests the importance ofnoncrop habitats as potential sources of primary virus inoculum. Viral disease onset followed peak aphid flights and further implicates A. glycines as a likely vector of viruses in commercial bean and other crops in Wisconsin.


Mating type control in Saccharomyces cerevisiae: a frameshift mutation at the common DNA sequence, X, of the HML alpha locus.
A mutation defective in the homothallic switching of mating type alleles, designated hml alpha-2, has previously been characterized. The mutation occurred in a cell having the HO MATa HML alpha HMRa genotype, and the mutant culture consisted of ca. 10% a mating type cells, 90% nonmater cells of haploid cell size, and 0.1% sporogenous diploid cells. Genetic analyses revealed that nonmater haploid cells have a defect in the alpha 2 cistron at the MAT locus. This defect was probably caused by transposition of a cassette originating from the hml alpha-2 allele by the process of the homothallic mating type switch. That the MAT locus of the nonmater cells is occupied by a DNA fragment indistinguishable from the Y alpha sequence in electrophoretic mobility was demonstrated by Southern hybridization of the EcoRI-HindIII fragment encoding the MAT locus with a cloned HML alpha gene as the probe. The hml alpha-2 mutation was revealed to be a one-base-pair deletion at the ninth base pair in the X region from the X and Y boundary of the HML locus. This mutation gave rise to a shift in the open reading frame of the alpha 2 cistron. A molecular mechanism for the mating type switch associated with the occurrence of sporogenous diploid cells in the mutant culture is discussed.


Mountain pine beetle host-range expansion threatens the boreal forest.
The current epidemic of the mountain pine beetle (MPB), an indigenous pest of western North American pine, has resulted in significant losses of lodgepole pine. The leading edge has reached Alberta where forest composition shifts from lodgepole to jack pine through a hybrid zone. The susceptibility of jack pine to MPB is a major concern, but there has been no evidence of host-range expansion, in part due to the difficulty in distinguishing the parentals and their hybrids. We tested the utility of a panel of microsatellite loci optimized for both species to classify lodgepole pine, jack pine and their hybrids using simulated data. We were able to accurately classify simulated individuals, and hence applied these markers to identify the ancestry of attacked trees. Here we show for the first time successful MPB attack in natural jack pine stands at the leading edge of the epidemic. This once unsuitable habitat is now a novel environment for MPB to exploit, a potential risk which could be exacerbated by further climate change. The consequences of host-range expansion for the vast boreal ecosystem could be significant.


Different sizes of restriction endonuclease fragments from the terminal repetitions of the herpes simplex virus type 1 genome latent in trigeminal ganglia of mice.
Trigeminal ganglion DNA from mice latently infected with herpes simplex virus type 1 was analysed by restriction enzyme digestion, agarose gel electrophoresis and blot hybridization to 32P-labelled viral DNA. Viral DNA from parental virions and from virions obtained as a consequence of reactivation by ganglion neurectomy were similarly analysed. The BamHI restriction fragments of parental and reactivated virions were almost indistinguishable from each other, and several of the larger BamHI fragments of viral DNA were also found in latently infected ganglion at unaltered sizes. In contrast, fractionation of EcoRI fragments of latently infected ganglion DNA by reverse phase column (RPC-5) chromatography, followed by gel electrophoresis and blot hybridization to a viral DNA probe from the S component terminal repetition, revealed the presence of several terminal fragments at discrete sizes ranging from 1 kb to 15 kb, quite unlike the 5.7 kb terminal EcoRI K fragment of virion-derived DNA. These results indicate that structural changes occur in the viral genome concomitantly with the establishment of latency, such as may result from extensive gene rearrangement or integration into cellular DNA.


Phenotypic side effects prediction by optimizing correlation with chemical and target profiles of drugs.
Despite technological progresses and improved understanding of biological systems, discovery of novel drugs is an inefficient, arduous and expensive process. Research and development cost of drugs is unreasonably high, largely attributed to the high attrition rate of candidate drugs due to adverse drug reactions. Computational methods for accurate prediction of drug side effects, rooted in empirical data of drugs, have the potential to enhance the efficacy of the drug discovery process. Identification of features critical for specifying side effects would facilitate efficient computational procedures for their prediction. We devised a generalized ordinary canonical correlation model for prediction of drug side effects based on their chemical properties as well as their target profiles. While the former is based on 2D and 3D chemical features, the latter enumerates a systems-level property of drugs. We find that the model incorporating chemical features outperforms that incorporating target profiles. Furthermore we identified the 2D and 3D chemical properties that yield best results, thereby implying their relevance in specifying adverse drug reactions.


Clinical spectrum of fungal infections after orthotopic liver transplantation.
During a 50-month period, we identified 91 episodes of fungal infection in 72 liver transplant recipients (23.8%). Candida species accounted for 83.5% of cases. Clinical patterns of fungal infections included disseminated infection (19), peritonitis (17), pneumonitis (15), multiple sites of colonization (13), fungemia (11), and other sites (16). The diagnosis of fungal infection was usually made in the first 2 months (84.7% of cases), at a mean time of 16 days after transplantation. Risk factors for fungal infections included retransplantation, Risk score, intraoperative transfusion requirement, urgent status, Roux limb biliary reconstruction (in adults), steroid dose, bacterial infections and antibiotic therapy, and vascular complications. Fungal infections were successfully treated with amphotericin B in 63 cases (74.1%) but were associated with diminished patient survival (50% vs 83.5%). Fungal infection is a frequent source of early morbidity and can be related to well-defined risk factors, suggesting the need for effective prophylaxis.


Development and Application of a Simple Plaque Assay for the Human Malaria Parasite Plasmodium falciparum.
Malaria is caused by an obligate intracellular protozoan parasite that replicates within and destroys erythrocytes. Asexual blood stages of the causative agent of the most virulent form of human malaria, Plasmodium falciparum, can be cultivated indefinitely in vitro in human erythrocytes, facilitating experimental analysis of parasite cell biology, biochemistry and genetics. However, efforts to improve understanding of the basic biology of this important pathogen and to develop urgently required new antimalarial drugs and vaccines, suffer from a paucity of basic research tools. This includes a simple means of quantifying the effects of drugs, antibodies and gene modifications on parasite fitness and replication rates. Here we describe the development and validation of an extremely simple, robust plaque assay that can be used to visualise parasite replication and resulting host erythrocyte destruction at the level of clonal parasite populations. We demonstrate applications of the plaque assay by using it for the phenotypic characterisation of two P. falciparum conditional mutants displaying reduced fitness in vitro.


Aberrant trafficking of the high-affinity choline transporter in AP-3-deficient mice.
The high-affinity choline transporter (CHT) is expressed in cholinergic neurons and efficiently transported to axon terminals where it controls the rate-limiting step in acetylcholine synthesis. Recent studies have shown that the majority of CHT is unexpectedly localized on synaptic vesicles (SV) rather than the presynaptic plasma membrane, establishing vesicular CHT trafficking as a basis for activity-dependent CHT regulation. Here, we analyse the intracellular distribution of CHT in the adaptor protein-3 (AP-3)-deficient mouse model mocha. In the mocha mouse, granular structures in cell bodies are intensely labelled with CHT antibody, indicating possible deficits in CHT trafficking from the cell body to the axon terminal. Western blot analyses reveal that CHT on SV in mocha mice is decreased by 30% compared with wild-type mice. However, no significant difference in synaptosomal choline uptake activity is detected, consistent with the existence of a large reservoir pool for CHT. To further characterize CHT trafficking, we established a PC12D-CHT cell line. In this line, CHT is found associated with a subpopulation of synaptophysin-positive synaptic-like microvesicles (SLMV). The amounts of CHT detected on SLMV are greatly reduced by treating the cell with agents that halt AP-dependent membrane trafficking. These results demonstrate that APs have important functions for CHT trafficking in neuronal cells.


Reef-associated fishes from the offshore reefs of western Campeche Bank, Mexico, with a discussion of mangroves and seagrass beds as nursery habitats.
A series of small emergent coral reefs and shallow, submerged coralliferous banks are scattered along the western edge of Campeche Bank (southwest Gulf of Mexico), 150-200 km offshore from the Yucatán Peninsula, Mexico. Here a reasonably comprehensive, annotated checklist of reef-associated fishes for one reef, Cayo Arcas (expanded from 162 to 209 species) is presented, with preliminary checklists of such fishes from three other emergent reefs (Cayo Arenas, Triángulo Oeste, Triángulo Este) and four submerged bank reefs (Banco Obispo Norte, Banco Obispo Sur, Banco Nuevo and Banco Pera). During 2017-18 a total of 260 species was observed or collected from those reefs, and previous studies and georeferenced museum records in the global aggregator Fishnet2 added another 101 shallow-living species recorded on or adjacent to those reefs. Some coral-reef fishes are thought to be strongly dependent on seagrass and mangrove areas as nursery habitats for maintenance of their local populations on reefs near to those habitats. The abundance of a number of such "nursery" species on these Campeche reefs indicates otherwise, as there are no seagrass- or mangrove habitats for reef fishes within ~ 150 km of the study reefs. Other isolated Caribbean-area reefs that lack mangroves and, in some cases, seagrasses, also support many such nursery species of reef-fishes.


Financial Strain, Religious Involvement, and Life Satisfaction Among Older Mexican Americans.
The purpose of this study is to see if financial strain affects the religious involvement and life satisfaction of older Mexican Americans. In the process, an effort was made to explore the factors that promote financial strain in this ethnic group, including immigration status and English language use. The data come from a nationwide survey of older Mexican Americans. Support was found for the following core relationships in the study model: (1) older adults who were born in Mexico will have less schooling; (2) less education will be associated with less frequent use of English; (3) less frequent use of English will be associated with greater financial strain; (4) greater financial strain leads to less formal involvement in the church; (5) older people who are less involved in the church will have a diminished sense of religious meaning; and (6) older adults with a lower sense of religious meaning will be less satisfied with life.


Operational definitions of asthma in studies on its aetiology.
The most popular way to define asthma based on questionnaires is to use definitions taken from cross-sectional international studies on asthma. These definitions may not, however, be optimal for future studies focusing on risk factors of asthma. The current authors, therefore, compared the performance of different operational definitions of asthma. The European Community Respiratory Health Study I was a cross-sectional study of 21,924 subjects aged between 25-44 yrs in 18 countries. Operational definitions of asthma compared included different combinations of symptoms of asthma and bronchial hyperresponsiveness. A continuous asthma score, ranging from 0-8, was defined as the sum of positive answers to eight main symptom questions. There was no threshold in the associations of asthma symptoms with severity or risk factors of asthma, which would have suggested a dichotomous definition of asthma. Using dichotomous definitions requiring the presence of several asthma symptoms strengthened associations with studied risk factors, and also increased the estimated specificity and positive predictive value. Using a continuous asthma score also improved the power of the analyses. In conclusion, dichotomous definitions of asthma yielding higher odds ratios are achieved by requiring positive responses to several questions on symptoms. However, symptoms of asthma are possibly best analysed as a continuous asthma score.


If I'm not hot, are you hot or not? Physical attractiveness evaluations and dating preferences as a function of one's own attractiveness.
Prior research has established that people's own physical attractiveness affects their selection of romantic partners. This article provides further support for this effect and also examines a different, yet related, question: When less attractive people accept less attractive dates, do they persuade themselves that the people they choose to date are more physically attractive than others perceive them to be? Our analysis of data from the popular Web site http://HOTorNOT.com suggests that this is not the case: Less attractive people do not delude themselves into thinking that their dates are more physically attractive than others perceive them to be. Furthermore, the results also show that males, compared with females, are less affected by their own attractiveness when choosing whom to date.


A lifetime of violence: results from an exploratory survey of Mexican women with HIV.
Despite recognition that traditional Mexican gender norms can contribute to the twin epidemics of violence against women and HIV, there is an absence of published literature on experiences of violence among Mexican women with HIV. We conducted a cross-sectional survey with 77 HIV-infected women from 21 of Mexico's 32 states to describe experiences of violence before and after HIV-diagnosis. We measured lifetime physical, sexual, and psychological violence; physical violence from a male partner in the previous 12 months; and physical and psychological violence related to disclosing an HIV diagnosis. Respondents reported ever experiencing physical violence (37.3%) and sexual violence (29.2%). Disclosure of HIV status resulted in physical violence for 7.2% and psychological violence for 26.5% of the respondents. This study underlines the need to identify and address past and current gender-based violence during pre- and post-HIV test counseling and as a systematic and integral part of HIV care.


The sorbin homology domain: a motif for the targeting of proteins to lipid rafts.
On phosphorylation of Cbl, the c-Cbl-associated protein (CAP)/Cbl complex dissociates from the insulin receptor and translocates to a lipid raft membrane fraction to form a ternary complex with flotillin. Deletion analyses of the CAP gene identified a 115-aa region responsible for flotillin binding. This region is homologous to the peptide sorbin and is referred to as the sorbin homology (SoHo) domain. This domain is present in two other proteins, vinexin and ArgBP2. Vinexin also interacted with flotillin, and deletion of its SoHo domain similarly blocked flotillin binding. The overexpression of a CAP mutant in which the SoHo domain had been deleted (CAPDeltaSoHo) prevented the translocation of Cbl to lipid rafts and subsequently blocked the recruitment of CrkII and C3G. Moreover, overexpression of CAPDeltaSoHo prevented the stimulation of glucose transport and GLUT4 translocation by insulin. These results suggest a mechanism for localization of signaling proteins to the lipid raft that mediates the compartmentalization of crucial signal transduction pathways.


Poly(aryleneethynylene)s (PAE) as paradigmatic sensor cores.
We describe poly(aryleneethynylene)s (PAE) as powerful sensor cores. We discuss concepts (super quenching, molecular wire effect, multivalency) that were developed using PAEs and also the relationship that connects side chain structure (polar, polyelectrolyte, etc., number of ionic groups per repeat, position) and optical properties such as quantum yields. In the second part of the review we discuss applications of PAEs in their interaction with sensor targets; metal cations, fluoride and other anions, explosives, proteins and whole cells being the target for PAEs, while cationic PAEs have been used for the transfection of eukaryotic cells with RNA.


Optic disc parameters and onset of glaucomatous field loss. II. Static screening criteria.
Stereoscopic fundus photographs of 17 abnormal eyes, taken in known temporal relationship to the onset of glaucomatous visual field loss, and 206 eyes of age- and race-matched controls were examined in randomized masked fashion. Width of the narrowest remaining disc rim, size of the vertical and horizontal physical cups, contour of the temporal and nasal slopes (vertical ovalness), and a newly described parameter, thickness of the nerve fiber layer as it crosses the disc rim, were all useful for distinguishing patients with impending or established visual field loss. None, however, was as effective as defects in the nerve fiber layer, the only parameter displaying sufficient promise as a clinical screening tool to warrant initiation of large-scale prospective evaluation.


First Report of Mango Malformation Disease Caused by Fusarium mangiferae in Sri Lanka.
Mango malformation disease (MMD) is one of the most devastating diseases causing severe economic losses to this crop worldwide. MMD has not been reported in Sri Lanka although the disease was reported in neighboring India over a century ago. Abnormal, thick, and fleshy mango panicles (40%) and proliferating stunted shoots (<1%) showing characteristic malformation symptoms were observed in Peradeniya-Kandy area (7°17'4.15" N, 80°38'14.08" E). Malformed inflorescences and vegetative shoots were collected during January to March and September to November, in 2008 through 2012. Pieces of malformed tissues were surface sterilized in 1% sodium hypochlorite and transferred to potato dextrose agar (PDA). The plates were incubated at 26 ± 2°C for 7 days. Monoconidial cultures of 41 isolates that resembled Fusarium spp. were obtained. Colonies showed white sparse aerial mycelium and magenta-dark purple pigmentation on the underside. Growth rate of the isolates averaged 3.67 mm/day in the dark at 25°C on PDA. To stimulate conidia development, Fusarium isolates were transferred to carnation leaf agar (CLA). Sympodially branched conidiophores bearing mono- and polyphialides with 2 to 3 conidiogenus openings originated erect and prostrate on aerial mycelium. Oval to allontoid, abundant microconidia were produced in false heads on mono- and polyphialides. Dimensions of aseptate conidia were 2.5 to 12.5 (6.47) × 1.25 to 3.8 (2.29) μm. Macroconidia were long and slender, 3 to 5 celled and 27.5 to 47.5 (38.59) × 2.5 to 5 (2.94) μm. Chlamydospores were absent. These characters are consistent for F. mangiferae. DNA was extracted from 30 monoconidial Fusarium isolates (1) and amplified with species-specific PCR primers 1-3F/R (forward: 5'-TGCAGATAATGAGGGTCTGC-3'; reverse: 5'-GGAACATTGGGCAAAACTAC-3') (3). Eight isolates from malformed inflorescences (I6, I13, I15, and I16) and malformed vegetative tissues (V1, V2, V3, and V4), were identified as F. mangiferae based on a 608-bp species-specific amplified DNA fragment. Pathogenicity of F. mangiferae isolates, I15 and V2, was tested on 1-year-old seedlings cv. Willard planted in 10-liter plastic pots. Conidia suspensions (107 conidia/ml of 0.1% water agar) were obtained from 10-day-old monoconidial cultures. Each isolate was inoculated onto 15 apical buds by placing drops (20 μl) of conidia (2). Both F. mangiferae isolates, I15 and V2, on artificial inoculation produced typical floral malformation symptoms in 40% of the buds, up to 10 weeks after inoculation. The Fusarium isolates recovered were identical in colony and mycelia morphology and conidia dimensions to the original F. mangiferae isolates. No Fusarium species were recovered from control flower buds. To our knowledge, this is the first report of MMD in the inflorescence and the vegetative shoots caused by F. mangiferae in Sri Lanka. Isolation of other Fusarium spp. that were not identified as F. mangiferae in this study suggests that additional Fusarium spp. may be associated with the MMD in Sri Lanka. Further studies are needed to confirm the identity of these Fusarium isolates, their role in MMD, and the distribution over the island. Since the disease is likely to drastically reduce productivity, measures will be required to protect 12,160 ha of mango cultivation from this devastating disease. References: (1) S. Freeman et al. Exp. Mycol. 17:309, 1993. (2) S. Freeman et al. Phytopathology 89:456, 1999. (3) Q. I. Zheng and R. C. Ploetz. Plant Pathol. 51:208, 2002.


Diversity of the cadmium-containing carbonic anhydrase in marine diatoms and natural waters.
A recent report of a novel carbonic anhydrase (CDCA1) with Cd as its metal centre in the coastal diatom Thalassiosira weissflogii has led us to search for the occurrence of this Cd enzyme (CDCA) in other marine phytoplankton and in the environment. Using degenerate primers designed from the published sequences from T. weissflogii and a putative sequence in the genome of Thalassiosira pseudonana, we show that CDCA is widespread in diatom species and ubiquitous in the environment. All detected genes share more than 64% amino acid identity with the CDCA of T. pseudonana. Analysis of the amino acid sequence of CDCA shows that the putative Cd binding site resembles that of beta-class carbonic anhydrases (CAs). The prevalence of CAs in diatoms that presumably contain Cd at their active site probably reflects the very low concentration of Zn in the marine environment and the difficulty in acquiring inorganic carbon for photosynthesis. The cdca primers developed in this study should be useful for detecting cdca genes in the field, and studying the conditions under which they are expressed.


Nitrite concentration influences the population structure of Nitrospira-like bacteria.
Chemolithoautotrophic nitrite oxidizers of the genus Nitrospira are a monophyletic but diverse group of organisms, are widely distributed in many natural habitats, and play a key role in nitrogen elimination during biological wastewater treatment. Phylogenetic analyses of cloned 16S rRNA genes and fluorescence in situ hybridization with newly developed rRNA-targeted oligonucleotide probes revealed coexistence of uncultured members of sublineages I and II of the genus Nitrospira in biofilm and activated sludge samples taken from nitrifying wastewater treatment plants. Quantitative microscopic analyses of their spatial arrangement relative to ammonia oxidizers in the biofilm and activated sludge flocs showed that members of the Nitrospira sublineage I occurred significantly more often in immediate vicinity to ammonia oxidizers than would be expected from random community assembly while such a relationship was not observed for Nitrospira sublineage II. This spatial distribution suggested a niche differentiation of these coexisting Nitrospira populations with respect to their preferred concentrations of nitrite. This hypothesis was tested by mathematical modelling of nitrite consumption and resulting nitrite gradients in nitrifying biofilms and by quantifying the abundance of sublineage I and II Nitrospira in activated sludge during incubations with nitrite in different concentrations. Consistent with the observed localization patterns, a higher nitrite concentration selected for sublineage I but suppressed sublineage II Nitrospira.


Enantioselective synthesis of α-aminosilanes by copper-catalyzed hydroamination of vinylsilanes.
The synthesis of α-aminosilanes by a highly enantio- and regioselective copper-catalyzed hydroamination of vinylsilanes is reported. The system employs Cu-DTBM-SEGPHOS as the catalyst, diethoxymethylsilane as the stoichiometric reductant, and O-benzoylhydroxylamines as the electrophilic nitrogen source. This hydroamination reaction is compatible with differentially substituted vinylsilanes, thus providing access to amino acid mimics and other valuable chiral organosilicon compounds.


Achieving High-Performance Room-Temperature Sodium-Sulfur Batteries With S@Interconnected Mesoporous Carbon Hollow Nanospheres.
Despite the high theoretical capacity of the sodium-sulfur battery, its application is seriously restrained by the challenges due to its low sulfur electroactivity and accelerated shuttle effect, which lead to low accessible capacity and fast decay. Herein, an elaborate carbon framework, interconnected mesoporous hollow carbon nanospheres, is reported as an effective sulfur host to achieve excellent electrochemical performance. Based on in situ synchrotron X-ray diffraction, the mechanism of the room temperature Na/S battery is proposed to be reversible reactions between S8 and Na2S4, corresponding to a theoretical capacity of 418 mAh g-1. The cell is capable of achieving high capacity retention of ∼88.8% over 200 cycles, and superior rate capability with reversible capacity of ∼390 and 127 mAh g-1 at 0.1 and 5 A g-1, respectively.


Longitudinal pancreatico-gastrostomy: an effective means of pain control in chronic pancreatitis.
To assess the effectiveness of longitudinal pancreatico-gastrostomy (LPG) in relieving intractable abdominal pain in patients of chronic pancreatitis (CP) with dilated main pancreatic duct (MPD). This prospective study was conducted from 1997-2005 at two university-affiliated hospitals in India. Ductal decompression by LPG was performed in 30 patients (26 males, 4 females) suffering from intractable pain due to CP. The operative outcomes were classified as satisfactory and unsatisfactory according to whether the patients were completely/almost completely relieved of pain or continued to be troubled by pain. The main outcome measures were pain-relief, postoperative morbidity, and mortality. There was no postoperative mortality. Morbidity included pancreatic fistula in one patient, which closed spontaneously, gastric hemorrhage in two, prolonged ileus in one and wound infection in another. Twenty eight patients (93%) patients could be followed up till the end, the mean follow-up period being 23.8 (range 3-96) months. Operative result was satisfactory (no pain or mild pain) in 23 (82%) and unsatisfactory (moderate to severe pain) in 5 (18%) patients. Complete pain relief was seen in 14 (50%) patients. The functional results, in terms of pain relief, were better in patients who had abstained from alcohol postoperatively. LPG is a good operative procedure to relieve intractable pain in patients of CP with an MPD diameter of at least 7 mm.


Novel roles of PAK1 in the heart.
Our work and others' over the past few years have led to the identification of new roles of PAK1 in cardiac physiology, such as the regulation of cardiac ion channel and actomyosin function. More recent studies have revealed that PAK1-deficient mice were vulnerable to cardiac hypertrophy and readily progress to failure under sustained pressure overload and susceptible to ischemia/reperfusion injury. Our further study indicated that the PAK1 activator FTY720 was able to prevent this pressure overload-induced hypertrophy in wild-type mice without compromising their cardiac functions. A cardiac protective effect against ischemia/reperfusion injury by FTY720 was also observed in both rat and mouse models by us and others. Thus, these studies suggest that PAK1 is more important in the heart than previously thought, in particular a therapeutic potential of PAK1 activators. In the future, in-depth investigations are required to further substantiate our hypotheses on mechanisms for PAK1 function in the heart and to explore a therapeutic potential of FTY720 and other PAK1 activators in heart disease conditions.


Circulating Levels of Calcitonin Gene-Related Peptide Are Lower in COVID-19 Patients.
To better understand the biology of COVID-19, we have explored the behavior of calcitonin gene-related peptide (CGRP), an angiogenic, vasodilating, and immune modulating peptide, in severe acute respiratory syndrome coronavirus 2 positive patients. Levels of CGRP in the serum of 57 COVID-19 patients (24 asymptomatic, 23 hospitalized in the general ward, and 10 admitted to the intensive care unit) and healthy donors (n = 24) were measured by enzyme-linked immunosorbent assay (ELISA). In addition, to better understand the physiological consequences of the observed variations, we investigated by immunofluorescence the distribution of receptor activity modifying protein 1 (RAMP1), one of the components of the CGRP receptor, in autopsy lung specimens. CGRP levels were greatly decreased in COVID-19 patients (P < 0.001) when compared to controls, and there were no significant differences due to disease severity, sex, age, or comorbidities. We found that COVID-19 patients treated with proton pump inhibitors had lower levels of CGRP than other patients not taking this treatment (P = 0.001). RAMP1 immunoreactivity was found in smooth muscle cells of large blood vessels and the bronchial tree and in the airways´ epithelium. In COVID-19 samples, RAMP1 was also found in proliferating type II pneumocytes, a common finding in these patients. The lower levels of CGRP should negatively impact the respiratory physiology of COVID-19 patients due to vasoconstriction, improper angiogenesis, less epithelial repair, and faulty immune response. Therefore, restoring CGRP levels in these patients may represent a novel therapeutic approach for COVID-19.